Drugs are usually delivered systemically by several methods including oral (tablets), parenteral (intravenous or intraperitoneally), topical (patches), pump (e.g. insulin pumps) administration. However, these methods expose the whole body to similar concentrations of the drug even though, usually, only a specific region of the body may require the drug. Also, the drug is usually cleared quite quickly from the body by the liver or kidneys so that, in order to maintain therapeutic concentrations of the drug, repeated drug administration is required. Furthermore, many areas of the body (such as bone or the disorganized growing regions of tumors) are poorly accessible to systemically administered drug so that high concentrations of the drug must be administered to reach therapeutic levels in the diseased tissue, resulting in especially high concentrations of the drug in all other non-diseased tissues. In summary, for many drugs systemic administration may be unnecessarily expensive and efficacy may be limited by dose limiting systemic drug toxicities and/or other factors.
Ideally, a drug should be delivered to the diseased site at a concentration that is optimal to treat the disease and be maintained at that concentration for the optimally required time. For example, diabetes is a systemic disease treated with insulin so that in some instances a pump system connected to an onboard blood glucose monitor that injects exactly the right amount of insulin to maintain optimal blood glucose levels might be considered an optimal drug delivery system.
Some drugs may be administered using implantable controlled release systems. For example, an injectable polymeric drug release system may be injected directly into a tumor and release the drug locally to kill cancer cells but the amount of drug released into the bloodstream may be insignificant so that systemic toxicity may be negligible. There are numerous examples in the literature describing injectable polymeric pastes or microspheres, for example, containing the anticancer drug paclitaxel. A gliadel™ wafer made from a polyanhydride containing an anticancer drug is approved for placement in brain tumor resection sites to kill residual cells. Stents, coated with paclitaxel in a polymer, may be placed in blood vessels to deliver the drug to the smooth muscle cells of the blood vessel to prevent proliferation and vessel closure.
With the exception of pumps, nearly all existing controlled release systems do not actually allow fine control of drug release. Usually the release profile is characterized by a burst phase of release followed by a continuous release at a slower rate. All rates may depend on geometry, injection conditions and/or other factors.
Improved controlled release systems would allow control of dose or timing of release and preferably both. This would allow external control of release as in an “on demand” system. Alternatively, an implanted system might be designed for a preprogrammed drug release without subsequent external control. This system might include, for example, a reservoir of drug implanted at a disease site with a built-in release system that provided drug at a schedule to fit a doctor's plan. These systems might also be used for radiotherapeutics whereby a sealed source was exposed to deliver a dose. Intra J et al, Journal of controlled release, 2008, 127, p 280-287 describe a system whereby a drug reservoir is covered with a PLGA membrane which degrades over time so that the drug may be released when the membrane degrades. The paper describes PLGA membranes with different degradation rates. This system acts as delayed release system where the delay may be controlled to some degree and therefore some scheduling of dosing may be achieved. The system does not allow for “on demand” drug release.
There has been much research completed in the area of microelectronic mechanical systems (MEMS) with drug release in mind. J. T. Santini, et al., “Microfabricated devices for the storage and selective exposure of chemicals and devices”, U.S. Pat. No. 6,849,463, described the possibility of microchips with drug reservoirs that have electronic release systems. Although many aspects of such devices have been described the biggest hurdle remains the power supply. Battery systems are not yet small enough to allow for on board power sources on microchips. This power is provided via connections to external sources. Such systems obviously limit the viability of the device. For example a device fitted in the ocular or be to release drug to the retina would require wires to be exposed outside the body. This is undesirable for many reasons. In certain disease settings (e.g. where a heart pacemaker has already been installed with an on board power supply) an auxiliary drug release system might take power form such a device. Such arrangements, however, at least in theory decrease the time required between battery changes, and therefore expose the patient to more frequent surgeries.
An external electromagnetic source has been used to generate electrical current in an implantable metallic coil. The current is then stored in a capacitor. Power is drawn from the capacitor when needed. The sizes of the coil, the capacitor and controlling circuitry dominate the overall drug delivery device volume. As with battery-powered devices, size and space become issues and potential barriers to use.
An improved strategy would allow for an external stimulus or stimuli to effect the drug release. Such stimuli might involve focused sources such as, for example, radioactive radiation, electromagnetic radiation (e.g. radio waves or microwaves) or heat whereby a cover over a reservoir was disturbed by the stimuli to expose the contents of the reservoir. Some systems have been described that attempt to use these methods. Other systems have described polymer matrices containing magnetic particles and drugs so that on the application of a magnetic field the movement of the particles may enhance drug release rates. However, such a system allows background drug release with acceleration of release upon magnetic stimulation so that the ability to control dose is very limited. Details of these previously described systems are included in the references below: A heat source is used to release drug from a reservoir in US20040121486A1. Magnetism is used to vibrate particles in a drug loaded polymer in US20070196281A1. Ultrasound is used to release drug from a reservoir in US2004032187A1. A catheter and pump system is described in US20040230182A1. MEMS based drug delivery systems have been described (U.S. Pat. Nos. 7,070,590, 6,551,838 and 6,537,256). Membranes sealing drug-containing reservoirs can be broken by heat or electrochemical degradation, however, the process needs a battery and heat from the device may damage the drug. Some include RF charging of a magnetic coil with a magnetic shield for better RF coupling (U.S. Pat. No. 6,850,803) and electromagnetically triggered porosity changes in polymers to release drugs (U.S. Pat. No. 5,830,207). Another patent (U.S. Pat. No. 6,689,380) focuses on providing electromagnetic fields to charge an RF coil and circuitry on a drug delivery device. However none of these patents are related to direct electromagnetic-to-mechanical energy translation for MEMS drug delivery devices.